Obsessive-compulsive disorder (OCD) is a chronic and debilitating anxiety disorder characterized by persistent intrusive thoughts, obsessions, compulsions, and repetitive habitual actions. It is estimated to affect 1-2% of the population, making it the fourth most common mental illness, yet current treatment options and therapies are limited and many OCD patients are unresponsive to first-line treatment. There is considerable evidence for the involvement of glutamatergic signaling in the cortico-striatal loop having a direct role in the abnormal behavioral inhibition and inappropriate compulsive or habitual actions symptomatic of the disorder. In preliminary experiments we found that mutant mice in which the genes encoding for kainate receptors, a modulatory glutamate receptor, are ablated have abnormal behaviors marked by elevated compulsive grooming and increased anxiety. This compulsive grooming and anxiety phenotype parallels that seen with several genetic mouse mutant strains displaying obsessive, self-injurious grooming behavior that have been proposed as mouse models of OCD. Kainate receptors are abundantly expressed in the striatum; however, their roles in regulating striatal synapses and circuits have not been defined. In this proposal we will take combined electrophysiological, optogenetic, behavioral and biochemical approaches to determine the cellular roles of kainate receptors in striatal circuits and their contribution to perseverative behaviors. Our hypothesis is that kainate receptor signaling in striatal spiny projection neurons (SPNs) plays a role in regulating synaptic transmission and plasticity. Loss of this regulation significantly impairs the output of the striatm and results in the maladaptive habitual and compulsive behavior. Thus, in specific aim 1 we will determine the contribution of kainate receptors to striatal synaptic function and plasticity ad test whether they regulate SPN synapses through a novel signaling mechanism discovered in our preliminary studies. In specific aim 2 we will determine whether interaction between kainate receptors and another known OCD-associated synaptic scaffold regulates synaptic kainate receptor function in the striatum. In specific aim 3 we will determine the circuit basis for compulsive behavior in mice by utilizing conditional genetic and pharmacological approaches to study behavior after specific manipulations. Together these studies will determine the cellular and circuit roles for kainate receptors in the striatum and their potential role in compulsive behaviors. This proposal will break new ground as the first to mechanistically associate the kainate receptor family to OCD, and to potentially provide a novel approachable target for the design of therapeutic strategies for this debilitating neuropsychiatric disorder. PUBLIC HEALTH RELEVANCE: Kainate receptors are glutamate-gated neurotransmitter receptors that are critical to synaptic signaling and plasticity. Pathophysiological activation of these receptors has been linked to several neuropsychiatric disorders including obsessive compulsive disorder (OCD). Using gene targeted mice we will determine how kainate receptors modulate circuits and synapses in brain regions known to be involved in habitual and compulsive behavior.